br Translational Considerations Targeting the AHR Pathway

Translational Considerations Targeting the AHR Pathway Modulating AHR function offers exciting therapeutic potential in host immunity and inflammation. However, the emerging concept of AHR function in a cell type-specific manner, combined with differences between AHR activation in cell culture in vitro and in animals in vivo, present challenges for targeting the AHR pathway pharmacologically. Therefore, any attempt to activate or inhibit AHR function in vivo using agonists (e.g., ligands) or antagonists (e.g., small-molecule inhibitors) must take into consideration the location and timing of administration of these AHR modulators. Because AHR is highly expressed in the barrier organs, local delivery of the AHR modulators may be able to achieve more precise and potent effects than systemic delivery. Indeed, it has been shown that local versus systemic delivery of the AHR ligand FICZ has opposite effects on experimental autoimmune encephalitis [21,23,24]. In addition, AHR is expressed by multiple cell types, and some side effects could thus be circumvented by manipulation of AHR function in a cell type-specific manner either in vitro or in vivo. Timing of administration of AHR modulators is also crucial given that AHR expression is minimal in naïve T dna staining but can be induced under particular conditions, for example by cytokines. Of note, unlike the effectiveness of administration of AHR ligands or depletion of AHR ligands by dietary restriction in young mice from birth, little or no impact on the ILC3 compartment was observed when these pharmacological manipulations were performed in adult mice [48,56]. Abundant food- or microbiota-derived ligands for AHR in adult mice might account for the lack of responses in these studies. The unresponsiveness to ligand manipulation might be apparent in cell types that have high expression levels of AHR (e.g., ILC3s) and/or in an environment in which endogenous AHR ligands are abundant, and where AHR expression/function is saturated and thus resistant to further pharmacological manipulation. Another consideration that needs our attention is that pharmacological agents may interfere with the AHR pathway in a sustained/prolonged or even harmful way. AHR activation leads to the expression of CYP enzymes which could metabolize many AHR ligands. The consequences of the enzyme-mediated degradation of AHR ligands could be complex and detrimental; for example, it is known that the AHR agonist benzo[a]pyrene can be metabolized into carcinogens by CYP1A1 and 1B1 [129].
Concluding Remarks Future research to understand the physiological and pathological role of AHR in the immune system must take into consideration the broad and inducible expression of AHR in various tissues, the elusive nature of its endogenous ligands, and the similarities and differences among cell culture, animal, and human studies (see Outstanding Questions). AHR exerts its function in a context-dependent and very much cell type-specific manner. In vivo studies of AHR function using ligands or other pharmacological means may be complicated by the diverse function of AHR in different tissues and cells. Thus, understanding the role of AHR in each cell type is crucial for the future design of therapeutics that target the AHR pathway pharmacologically. Considering the crosstalk between the AHR pathway and other cytokine/metabolic pathways, mechanistic understanding of the action of AHR will benefit from global analysis of AHR-directed transcriptome, cistrome, interactome, and metabolome by next-generation sequencing and other technologies in primary immune cells.
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